PHY906 is a traditional Chinese herbal medicine that has been used in the Orient for nearly 2000 years to treat diarrhea and nausea/vomiting. Our research group has developed a novel cGMP formulation of PHY906 that has been shown to be free of heavy metals and any other contaminants. We have characterized the preclinical activity of PHY906 as a modulator of cytotoxicity of anticancer agents and a cytoprotective agent of chemotherapy. An extensive series of pre-clinical in vivo studies using mouse xenograft models have shown that this herbal medicine can enhance the antitumor activity of a broad range of anticancer agents, including the topo I inhibitor irinotecan, and reduce toxicity. Preliminary results from an initial phase l/lla clinical study with PHY906 in combination with IFL chemotherapy in the front-line treatment of advanced CRC patients showed that PHY906 was able to effectively reduce the Gl toxicities of diarrhea and nausea/vomiting as well as overall fatigue. These observations suggested that PHY906 can reduce the toxicities associated with irinotecan-based chemotherapy. However, this initial pilot study was unable to determine the potential effect of PHY906 on the clinical efficacy of irinotecan chemotherapy. Our hypothesis is that PHY906 will be able to enhance the safety profile associated with irinotecan chemotherapy and maintain, if not improve, the clinical activity associated with this anticancer agent. To directly address this hypothesis, we plan to conduct a randomized, double-blind, placebo-controlled phase II clinical trial to investigate the effects ofthe Chinese herbal medicine PHY906 on the toxicity, quality of life, and clinical efficacy of irinotecan monotherapy in the treatment of patients with advanced CRC in the second-line setting. Patients will be randomized to receive the control arm of irinotecan plus placebo or to the experimental arm of irinotecan plus PHY906. As part of this clinical study, 3 specific aims are proposed: Aim 1 will determine the effect of PHY906 on the safety profile of irinotecan monotherapy with a focus on Gl toxicity, in the form of diarrhea and nausea/vomiting, as well as myelosuppression and fatigue. Aim 2 will investigate the effect of PHY906 on overall quality of life associated with irinotecan monotherapy using well-established and validated patient-reported assessment tools. Aim 3 will investigate the effect of PHY906 on the clinical efficacy of irinotecan monotherapy with respect to overall response rates, progression-free survival, and overall survival.